Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
Key Laboratory of Cardiovascular Proteomics of Shandong Province, Department of Geriatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
EMBO Rep. 2022 Feb 3;23(3):e53373. doi: 10.15252/embr.202153373. Epub 2022 Jan 7.
Mammalian cells utilize Akt-dependent signaling to deploy intracellular Glut4 toward cell surface to facilitate glucose uptake. Low-density lipoprotein receptor (LDLR) is the cargo receptor mediating endocytosis of apolipoprotein B-containing lipoproteins. However, signaling-controlled regulation of intracellular LDLR trafficking remains elusive. Here, we describe a unique amino acid stress response, which directs the deployment of intracellular LDLRs, causing enhanced LDL endocytosis, likely via Ca and calcium/calmodulin-dependent protein kinase II-mediated signalings. This response is independent of induction of autophagy. Amino acid stress-induced increase in LDL uptake in vitro is comparable to that by pravastatin. In vivo, acute AAS challenge for up to 72 h enhanced the rate of hepatic LDL uptake without changing the total expression level of LDLR. Reducing dietary amino acids by 50% for 2 to 4 weeks ameliorated high fat diet-induced hypercholesterolemia in heterozygous LDLR-deficient mice, with reductions in both LDL and VLDL fractions. We suggest that identification of signaling-controlled regulation of intracellular LDLR trafficking has advanced our understanding of the LDLR biology, and may benefit future development of additional therapeutic strategies for treating hypercholesterolemia.
哺乳动物细胞利用 Akt 依赖性信号通路将细胞内的 Glut4 募集到细胞膜表面，以促进葡萄糖摄取。低密度脂蛋白受体 (LDLR) 是介导载脂蛋白 B 脂蛋白内吞作用的货物受体。然而，细胞内 LDLR 运输的信号控制调节仍不清楚。在这里，我们描述了一种独特的氨基酸应激反应，该反应指导细胞内 LDLR 的募集，导致 LDL 内吞作用增强，可能通过 Ca 和钙/钙调蛋白依赖性蛋白激酶 II 介导的信号转导。这种反应不依赖于自噬的诱导。体外氨基酸应激诱导的 LDL 摄取增加与普伐他汀相当。在体内，急性 AAS 挑战长达 72 小时可增强肝脏 LDL 摄取率，而不改变 LDLR 的总表达水平。通过减少 2 至 4 周的饮食中氨基酸含量的 50%，可改善杂合子 LDLR 缺陷型小鼠的高脂肪饮食诱导的高胆固醇血症，降低 LDL 和 VLDL 两部分。我们认为，鉴定细胞内 LDLR 运输的信号控制调节已经提高了我们对 LDLR 生物学的理解，并可能有益于未来开发治疗高胆固醇血症的额外治疗策略。
